Rotavirus Vaccines Part II: Raising the Bar for Vaccine Safety Studies



Rotaviruses are one of the important causes of disease and death worldwide. For this reason, there has been a great deal of public and private interest in developing a vaccine. Unfortunately, because of a rare adverse event associated with the first marketed rotavirus vaccine, subsequent vaccines have been difficult to develop.


Vaccine Adverse Event Reporting System Rare Adverse Event Yellow Fever Vaccine Intestinal Mucosal Surface Heterotypic Protection 
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  1. 1.
    de Zoysa I, Feachem RG. Interventions for the control of diarrhoeal diseases among young children: rotavirus and cholera immunization. Bull World Health Organ 63:569–583, 1985.PubMedGoogle Scholar
  2. 2.
    Kapikian AZ, Hoshino Y, Chanock RM. Rotaviruses. In Fields BN, Knipe DM, Howley PM (eds). Fields Virology (4th ed). Vol. 2. Philadelphia, Lippincott–Raven, 2001, pp 1787–1833.Google Scholar
  3. 3.
    Brandt CD, Kim HW, Rodriguez JO, et al. Pediatric viral gastroenteritis during eight years of study. J Clin Microbiol 18:71–78, 1983.PubMedGoogle Scholar
  4. 4.
    Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis 174(suppl 1):S5–S11, 1996.PubMedCrossRefGoogle Scholar
  5. 5.
    Kilgore PE, Holman RC, Clarke MJ, Glass RI. Trends of diarrheal disease–associated mortality in U.S. children, 1968 through 1991. JAMA 274:1143–1148, 1995.Google Scholar
  6. 6.
    Jin S, Kilgore PK, Holman RC, et al. Trends in hospitalizations for diarrhea in United States children from 1979–1992: estimates of the morbidity associated with rotavirus. Pediatr Infect Dis J 15:397–404, 1996.PubMedCrossRefGoogle Scholar
  7. 7.
    Smith J, Haddix A, Teutsch S, Glass RI. Cost effectiveness analysis of a rotavirus immunization program for the United States. Pediatrics 96:609–615, 1995.PubMedGoogle Scholar
  8. 8.
    Huilan S, Zhen LG, Mathan MM, et al. Etiology of acute diarrhoea among children in developing countries: a multicentre study in five countries. Bull World Health Organ 69:549–555, 1991.PubMedGoogle Scholar
  9. 9.
    Levine MM, Losonsky G, Herrington D, et al. Pediatric diarrhea: the challenge of prevention. Pediatr Infect Dis 5(suppl):S29–S43, 1986.PubMedCrossRefGoogle Scholar
  10. 10.
    Cook SM, Glass RI, LeBaron CW, Ho M-S. Global seasonality of rotavirus infections. Bull World Health Organ 68:171–177, 1990.PubMedGoogle Scholar
  11. 11.
    Bern C, Martines J, de Zoysa I, Glass RI. The magnitude of the global problem of diarrhoeal disease: a ten-year update. Bull World Health Organ 70:705–714, 1992.PubMedGoogle Scholar
  12. 12.
    Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349:1436–1442, 1997.PubMedCrossRefGoogle Scholar
  13. 13.
    Walsh JA, Warren KS. Selective primary health care: an interim strategy for disease control in developing countries. N Engl J Med 301:967–974, 1979.PubMedCrossRefGoogle Scholar
  14. 14.
    Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull World Health Organ 60:605–613, 1982.PubMedGoogle Scholar
  15. 15.
    Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9:565-572.PubMedGoogle Scholar
  16. 16.
    Tallett S, MacKenzie C, Middleton P, et al. Clinical, laboratory, and epidemiologic features of a viral gastroenteritis in infants and children. Pediatrics 60:217–222, 1977.PubMedGoogle Scholar
  17. 17.
    Carr M, McKendrick D, Spyridakis T. The clinical features of infantile gastroenteritis due to rotavirus. Scand J Infect Dis 8:241–243, 1978.Google Scholar
  18. 18.
    Kovacs A, Chan L, Hotrakitya C, et al. Rotavirus gastroenteritis: clinical and laboratory features and use of the Rotazyme test. Am J Dis Child 141:161–166, 1987.PubMedGoogle Scholar
  19. 19.
    Rodriguez W, Kim H, Arrobio J, et al. Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children. J Pediatr 91:188–193, 1977.PubMedCrossRefGoogle Scholar
  20. 20.
    Estes M. Rotaviruses and their replication. In Fields BN, Knipe DM, Howley PM (eds). Fields Virology (4th ed). Vol. 2. Philadelphia, Lippincott–Raven, 2001, pp 1747–1786.Google Scholar
  21. 21.
    Larralde G, Li B, Kapikian AZ, Gorziglia M. Serotype-specific epitopes present on the VP 8 subunit of rotavirus VP 4 protein. J Virol 65:3213–3218, 1991.PubMedGoogle Scholar
  22. 22.
    Gorziglia MKY, Green K, Nishikawa K, et al. Sequence of the fourth gene of human rotaviruses recovered from asymptomatic or symptomatic infections. J Virol 62:2979–2984, 1988.Google Scholar
  23. 23.
    Hoshino Y, Wyatt RG, Greenberg HB. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque reduction neutralization. J Infect Dis 149:694–702, 1984.PubMedCrossRefGoogle Scholar
  24. 24.
    Svensson L, Sheshbaradaran H, Visikari T, et al. Immune response to rotavirus polypeptides after vaccination with heterologous rotavirus vaccines (RIT 4237, RRV-1). J Gen Virol 68:1993–1999, 1987.PubMedCrossRefGoogle Scholar
  25. 25.
    Ward RL, Knowlton DR, Schiff GM, et al. Relative concentrations of serum neutralizing antibody to VP 3 and VP 7 proteins in adults infected with a human rotavirus. J Virol 62:1543–1549, 1989.Google Scholar
  26. 26.
    Ward RL, Knowlton DR, Greenberg HG, et al. Serum-neutralizing antibody to VP 4 and VP 7 proteins in infants following vaccination with WC3 bovine rotavirus. J Virol 64:2687–2691, 1990.PubMedGoogle Scholar
  27. 27.
    Matsui S, Mackow E, Greenberg H. Molecular determinants of rotavirus neutralization and protection. Adv Virus Res 36:181–214, 1989.PubMedCrossRefGoogle Scholar
  28. 28.
    Estes MK, Cohen J. Rotavirus gene structure and function. Microbiol Rev 53:410–449, 1989.PubMedGoogle Scholar
  29. 29.
    Bishop R, Barnes G, Cipriani E, Lund J. Clinical immunity after neonatal rotavirus infection: a prospective longitudinal study in young children. N Engl J Med 309:72–76, 1983.PubMedCrossRefGoogle Scholar
  30. 30.
    Bernstein DI, Sander DS, Smith VE, et al. Protection from rotavirus reinfection: 2-year prospective study. J Infect Dis 164:277–283, 1991.PubMedCrossRefGoogle Scholar
  31. 31.
    Ward RL, Bernstein D. Protection against rotavirus disease after natural infection. J Infect Dis 169:900–904, 1994.PubMedCrossRefGoogle Scholar
  32. 32.
    Fisher TK, Valentiner-Branth P, Steinsland H, et al. Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, West Africa. J Infect Dis 186: 593–597, 2002.Google Scholar
  33. 33.
    Yolken R, Wyatt R, Zissis G. Epidemiology of human rotavirus types 1 and 2 as studied by enzyme-linked immunosorbent assay. N Engl J Med 299:1156–1161, 1978.PubMedCrossRefGoogle Scholar
  34. 34.
    Black R, Greenberg H, Kapikian A, et al. Acquisition of serum antibody to Norwalk virus and rotavirus in relation to diarrhea in a longitudinal study of young children in rural Bangladesh. J Infect Dis 145:483–489, 1982.PubMedCrossRefGoogle Scholar
  35. 35.
    Mata L, Simhon A, Urratia J, et al. Epidemiology of rotaviruses in a cohort of 45 Guatemalan Mayan Indian children observed from birth to the age of three years. J Infect Dis 148:452–461, 1983.PubMedCrossRefGoogle Scholar
  36. 36.
    Chiba S, Nakata S, Urasawa T, et al. Protective effect of naturally acquired homotypic and heterotypic rotavirus antibodies. Lancet 1:417–421, 1986.CrossRefGoogle Scholar
  37. 37.
    Linhares A, Gabbay Y, Mascarenhas J, et al. Epidemiology of rotavirus subgroups and serotypes in Belem, Brazil: a three-year study. Ann Inst Pasteur (Virol) 139:89–99, 1988.Google Scholar
  38. 38.
    Georges-Courbot M, Monges J, Beraud-Cassel A, et al. Prospective longitudinal study of rotavirus infections in children from birth to two years of age in Central Africa. Ann Inst Pasteur (Virol) 139:421–428, 1988.Google Scholar
  39. 39.
    Friedman M, Gaul A, Sarov B, et al. Two sequential outbreaks of rotavirus gastroenteritis: evidence for symptomatic and asymptomatic reinfection. J Infect Dis 158:814–822, 1988.PubMedCrossRefGoogle Scholar
  40. 40.
    Grinstein S, Gomez J, Bercovich J, Biscorn E. Epidemiology of rotavirus infection and gastroenteritis in prospectively monitored Argentine families with young children. Am J Epidemiol 130:300–308, 1989.PubMedGoogle Scholar
  41. 41.
    Reves R, Hossain M, Midthun K, et al. An observational study of naturally acquired immunity in a cohort of 363 Egyptian children. Am J Epidemiol 130:981–988, 1989.PubMedGoogle Scholar
  42. 42.
    O’Ryan M, Matson D, Estes M, et al. Molecular epidemiology of rotavirus in young children attending day care centers in Houston. J Infect Dis 162:810–816, 1990.PubMedCrossRefGoogle Scholar
  43. 43.
    DeChamps C, Laveran H, Peigue-Lafeville J, et al. Sequential rotavirus infections: characterization of serotypes and electropherotypes. Res Virol 142:39–45, 1991.CrossRefGoogle Scholar
  44. 44.
    Matson DO, O’Ryan ML, Herrera I, et al. Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis 167:577–583, 1993.PubMedCrossRefGoogle Scholar
  45. 45.
    Coulson B, Grimwood K, Hudson I, et al. Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol 30:1678–1684, 1992.PubMedGoogle Scholar
  46. 46.
    Moser CA, Coffin SE, Cookinham S, Offit PA. Relative importance of rotavirus-specific effector and memory B cell responses in protection against challenge. J Virol 72:1108–1114, 1998.PubMedGoogle Scholar
  47. 47.
    Kapikian AZ, Midthun K, Hoshino Y, et al. Rhesus rotavirus: a candidate vaccine for prevention of human rotavirus disease. In Lerner RA, Chanock RM, Brown F (eds). Molecular and Chemical Basis of Resistance to Parasitic, Bacterial, and Viral Diseases. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1985, pp 357–367.Google Scholar
  48. 48.
    Flores J, Perez-Schael I, Gonzalez M, et al. Protection against severe rotavirus diarrhea by rhesus rotavirus vaccine in Venezuelan children. Lancet 1:882–884, 1987.PubMedCrossRefGoogle Scholar
  49. 49.
    Vesikari T, Rautanen T, Varis T, et al. Rhesus rotavirus candidate vaccine: clinical trial in children vaccinated between 2 and 5 months of age. Am J Dis Child 144:285–289, 1990.PubMedGoogle Scholar
  50. 50.
    Gothefors L, Wadell G, Juto P, et al. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis 159:753–757, 1989.PubMedCrossRefGoogle Scholar
  51. 51.
    Santosham M, Letson GW, Wolff M, et al. A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population. J Infect Dis 163:483–487, 1991.PubMedCrossRefGoogle Scholar
  52. 52.
    Christy C, Madore HP, Pichichero ME, et al. Field trial of rhesus rotavirus vaccine in infants. Pediatr Infect Dis J 7:645–650, 1988.PubMedCrossRefGoogle Scholar
  53. 53.
    Rennels MB, Losonsky GA, Young AE, et al. An efficacy trial of the rhesus rotavirus vaccine in Maryland. Am J Dis Child 144:601–604, 1990.PubMedGoogle Scholar
  54. 54.
    Clark HF, Furukawa T, Bell LM, et al. Immune response of infants and children to low-­passage bovine rotavirus (strain WC3). Am J Dis Child 140:350–356, 1986.PubMedGoogle Scholar
  55. 55.
    Clark HF, Borian FE, Bell LM, et al. Protective effect of WC3 vaccine against rotavirus diarrhea in infants during a predominantly serotype 1 rotavirus season. J Infect Dis 158:570–587, 1988.PubMedCrossRefGoogle Scholar
  56. 56.
    Bernstein DI, Smith VE, Sander DS, et al. Evaluation of WC3 rotavirus vaccine and correlates of protection in healthy infants. J Infect Dis 162:1055–1062, 1990.PubMedCrossRefGoogle Scholar
  57. 57.
    Georges-Courbot MC, Monges J, Siopathis MR, et al. Evaluation of the efficacy of a low-passage bovine rotavirus (strain WC3) vaccine in children in Central Africa. Res Virol 142:405–411, 1991.PubMedCrossRefGoogle Scholar
  58. 58.
    Hoshino Y, Sereno MM, Midthun K, et al. Independent segregation of two antigenic specificities (VP3 and VP7) involved in neutralization of rotavirus infectivity. Proc Natl Acad Sci U S A 82:8701–8704, 1985.PubMedCrossRefGoogle Scholar
  59. 59.
    Offit PA, Blavat G. Identification of the two rotavirus genes determining neutralization specificities. J Virol 57:376–378, 1986.PubMedGoogle Scholar
  60. 60.
    Offit PA, Clark HF, Blavat G, Greenberg HB. Reassortant rotaviruses containing structural proteins VP3 and VP7 from different parents induce antibodies protective against each parental serotype. J Virol 60:491–496, 1986.PubMedGoogle Scholar
  61. 61.
    Hoshino Y, Sereno MM, Kapikian AZ, et al. Genetic determinants of rotavirus virulence studied in gnotobiotic piglets. In Vaccines 93. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1993, pp 277–282.Google Scholar
  62. 62.
    Kapikian AZ, Hoshino Y, Chanock RM, Perez-Schael I. Efficacy of a quadrivalent rhesus rotavirus–based human rotavirus vaccine aimed at preventing severe rotavirus diarrhea in infants and young children. J Infect Dis 174(suppl 1):S65–S72, 1996.PubMedCrossRefGoogle Scholar
  63. 63.
    Stuker G, Oshiro LS, Schmidt NH. Antigenic comparisons of two new rotaviruses from rhesus monkeys. J Clin Microbiol 11:202–203, 1980.PubMedGoogle Scholar
  64. 64.
    Nishikawa K, Hoshino Y, Taniguchi K, et al. Rotavirus v.p. 7 neutralization epitopes of serotype 3 strains. Virology 171:503–515, 1989.Google Scholar
  65. 65.
    Centers for Disease Control and Prevention. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children: recommendations of the Advisory Committee on Immunization Practices. MMWR 48:1–23, 1999.Google Scholar
  66. 66.
    Committee on Infectious Diseases, American Academy of Pediatrics. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics 102:1483–1491, 1998.Google Scholar
  67. 67.
    Centers for Disease Control and Prevention. Intussusception among recipients of rotavirus vaccine—United States, 1998–1999. MMWR 48:577–581, 1999.Google Scholar
  68. 68.
    Committee on Infectious Diseases, American Academy of Pediatrics. Possible association of intussusception with rotavirus vaccination. Pediatrics 104:575, 1999.Google Scholar
  69. 69.
    Murphy TV, Garguillo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 344:564–572, 2001.PubMedCrossRefGoogle Scholar
  70. 70.
    Kramarz P, France EK, Destefano F, et al. Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J 20:410–416, 2001.PubMedCrossRefGoogle Scholar
  71. 71.
    Chang H-G, Smith PF, Ackelsberg J, et al. Intussusception, rotavirus diarrhea, and rotavirus vaccine use among children in New York State. Pediatrics 108:54–60, 2001.PubMedCrossRefGoogle Scholar
  72. 72.
    Simonsen L, Morens DM, Elixhauser A, et al. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet 358:1224–1229, 2001.PubMedCrossRefGoogle Scholar
  73. 73.
    Chang E, Zangwill KM, Lee H, Ward JI. Lack of association between rotavirus infection and intussusception: implications for use of attenuated rotavirus vaccines. Pediatr Infect Dis J 21:97–102, 2002.PubMedCrossRefGoogle Scholar
  74. 74.
    Lin Z, Cohen P, Nissan A, et al. Bacterial wall lipopolysaccharide as a cause of intussusception in mice. J Pediatr Gastroenterol Nutr 27:301–305, 1998.PubMedCrossRefGoogle Scholar
  75. 75.
    Nissan A, Zhang J, Lin Z, et al. The contribution of inflammatory mediators and nitric oxide to lipopolysaccharide-induced intussusception in mice. J Surg Res 69:205–207, 1997.PubMedCrossRefGoogle Scholar
  76. 76.
    Ciarlet M, Estes MK, Conner ME. Simian rhesus rotavirus is a unique heterologous (non-lapine) rotavirus strain capable of productive replication and horizontal transmission in rabbits. J Gen Virol 81:1237–1249, 2000.PubMedGoogle Scholar
  77. 77.
    Uhnoo I, Riepenhoff-Talty M, Dharakul T, et al. Extramucosal spread and development of hepatitis with rhesus rotavirus in immunodeficient and normal mice. J Virol 64:361–368, 1990.PubMedGoogle Scholar
  78. 78.
    Moser CA, Dolfi D, DiVietro ML, et al. Hypertrophy, hyperplasia, and infectious virus in gut-associated lymphoid tissue of mice after oral inoculation with simian-human or bovine-human reassortant rotavirus. J Infect Dis 2001;183:1108-1111.PubMedCrossRefGoogle Scholar
  79. 79.
    Ward RL, Dinsmore AM, Goldbery G, et al. Shedding of rotavirus after administration of the tetravalent rhesus rotavirus vaccine. Pediatr Infect Dis J 17:386–390, 1998.PubMedCrossRefGoogle Scholar
  80. 80.
    Centers for Disease Control and Prevention: Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices. Morbid Mortal Week Rep 58:1-24, 2009.Google Scholar
  81. 81.
    Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23-33.PubMedCrossRefGoogle Scholar
  82. 82.
    Centers for Disease Control and Prevention. Postmarketing monitoring of intussusception after RotaTeq vaccination—United States, February 1, 2006-February 15, 2007. MMWR 56: 218-222, 2007.Google Scholar
  83. 83.
    Centers for Disease Control and Prevention. Delayed onset and diminished magnitude of rotavirus activity—United States, November 2007-May 2008. MMWR 57:1-2, 2008.Google Scholar
  84. 84.
    Gouveia, M. Personal communication.Google Scholar
  85. 85.
    Ruiz-Palacios GM, Perez-Schael I, Veláquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. New Eng J Med 354 (1):11-21, 2006.PubMedCrossRefGoogle Scholar
  86. 86.
    Vesikari T, Prymula R, Schuster V, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 370: 1757-1763, 2007.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Children’s Hospital of PhiladelphiaPhiladelphiaUSA

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